M ultisystem infl ammatory syndrome (MIS) in children (MIS-C) and adults (MIS-A) are febrile syndromes with elevated infl ammatory markers that usually manifest 2-6 weeks after a severe acute respiratory syndrome 2 (SARS-CoV-2) infection (1-3). The Brighton Collaboration Case Defi nition for MIS-C/A was recently published to be used in the evaluation of patients after SARS-CoV-2 immunization (3); some scientists are concerned that vaccination against SARS-CoV-2 can trigger MIS-C/A. We report 6 cases of MIS from a large integrated health system in Southern California, USA; 3 of those patients received SARS-CoV-2 vaccination shortly before seeking care for MIS. All 6 patients met the Brighton Collaboration Level 1 of diagnostic certainty for a defi nitive case and had MIS illness onset between January 15-February 15, 2021. The Chief Compliance Offi cer for the Southern California Permanente Medical Group reviewed this case series and confi rmed that it was compliant with the Health Insurance Portability and Accountability Act for publication. The StudyPatient 1 was a 20-year-old Hispanic woman who sought care for 3 days of a diffuse body rash, tac-tile fever, sore throat, mild neck discomfort, and fatigue. There was no cough, congestion, headache, or abdominal pain. She had vomiting and diarrhea, which had subsided 8 days before admission. She received her fi rst dose of SARS-CoV-2 vaccine 15 days before admission. She had no known coronavirus disease (COVID-19) exposure but was SARS-CoV-2 PCR and nucleocapsid IgG positive. She was hypotensive at arrival to the emergency department, requiring inotropic support. She had elevated troponin and brain natriuretic peptide (BNP) with a left ventricular ejection fraction initially mildly reduced at 45% but 30%-35% the following day. She responded well to therapy with intravenous immunoglobulin (IVIG) and methylprednisolone (Table 1).Patient 2 was a 40-year-old Hispanic man who sought care after 6 days of episodic fevers up to 101.7°F. Associated symptoms included dyspnea on exertion, headache, neck pain, lethargy, abdominal pain, and diarrhea. No chest pain was present. He had a history of SARS-CoV-2 vaccination and laboratory-confi rmed mild to moderate COVID-19, both within 48 days before seeking care (Figure). His exam was notable for sweats, diffuse abdominal pain on palpation, tachycardia, and tachypnea. Patient 2 fulfi lled Brighton Level 1 criteria for MIS-A with documented fevers, gastrointestinal and neurologic symptoms, elevated infl ammatory and cardiac markers, and electrocardiogram changes that were concerning for myocarditis (3). He responded well to treatment with dexamethasone (Table 1).Patient 3 was an 18-year-old Asian American man who sought care at the emergency department with a history of 3 days of fever as high as 104°F with headache, vomiting, diarrhea, and abdominal cramping (Figure). He denied any upper respiratory symptoms. He had a history of a laboratoryconfi rmed COVID-19 infection 6 weeks before the onset of symptoms and received the fi rst d...

OBJECTIVE Stereotactic radiosurgery (SRS) is an important alternative management option for patients with small- and medium-sized vestibular schwannomas (VSs). Its use in the treatment of large tumors, however, is still being debated. The authors reviewed their recent experience to assess the potential role of SRS in larger-sized VSs. METHODS Between 2000 and 2014, 35 patients with large VSs, defined as having both a single dimension > 3 cm and a volume > 10 cm, underwent Gamma Knife radiosurgery (GKRS). Nine patients (25.7%) had previously undergone resection. The median total volume covered in this group of patients was 14.8 cm (range 10.3-24.5 cm). The median tumor margin dose was 11 Gy (range 10-12 Gy). RESULTS The median follow-up duration was 48 months (range 6-156 months). All 35 patients had regular MRI follow-up examinations. Twenty tumors (57.1%) had a volume reduction of greater than 50%, 5 (14.3%) had a volume reduction of 15%-50%, 5 (14.3%) were stable in size (volume change < 15%), and 5 (14.3%) had larger volumes (all of these lesions were eventually resected). Four patients (11.4%) underwent resection within 9 months to 6 years because of progressive symptoms. One patient (2.9%) had open surgery for new-onset intractable trigeminal neuralgia at 48 months after GKRS. Two patients (5.7%) who developed a symptomatic cyst underwent placement of a cystoperitoneal shunt. Eight (66%) of 12 patients with pre-GKRS trigeminal sensory dysfunction had hypoesthesia relief. One hemifacial spasm completely resolved 3 years after treatment. Seven patients with facial weakness experienced no deterioration after GKRS. Two of 3 patients with serviceable hearing before GKRS deteriorated while 1 patient retained the same level of hearing. Two patients improved from severe hearing loss to pure tone audiometry less than 50 dB. The authors found borderline statistical significance for post-GKRS tumor enlargement for later resection (p = 0.05, HR 9.97, CI 0.99-100.00). A tumor volume ≥ 15 cm was a significant factor predictive of GKRS failure (p = 0.005). No difference in outcome was observed based on indication for GKRS (p = 0.0761). CONCLUSIONS Although microsurgical resection remains the primary management choice in patients with VSs, most VSs that are defined as having both a single dimension > 3 cm and a volume > 10 cm and tolerable mass effect can be managed satisfactorily with GKRS. Tumor volume ≥ 15 cm is a significant factor predicting poor tumor control following GKRS.

Colorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

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Hypothyroidism and chronic kidney disease (CKD) are highly prevalent conditions with a potential mechanistic link. We sought to determine whether hypothyroidism is associated with CKD among a large diverse community-based cohort. A cross-sectional study was performed (January 1, 1990–December 31, 2017) within a large integrated health system. Individuals age ≥55 years of age with outpatient measurements of thyroid stimulating hormone (TSH) and ≥2 serum creatinine values were included. Hypothyroidism was defined as TSH >4 mIU/L and/or receipt of thyroid hormone replacement and further categorized as hypothyroid status: TSH >4 mcIU/mL and attenuated-hypothyroid status: TSH <4 mcIU/mL with receipt of thyroid hormone replacement. Euthyroidism was defined as TSH <4 mIU/L and no thyroid hormone replacement. Our primary measure was CKD defined as an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. Multivariable logistic regression adjusting for age, sex, race, and comorbidities was used to estimate odds ratios (OR) for CKD by thyroid status. Among 378,101 individuals, 114,872 (30.4%) had hypothyroidism among whom 31,242 and 83,630 had hypothyroid and attenuated-hypothyroid statuses, respectively. Individuals with hypothyroidism had a CKD OR (95%CI) of 1.25 (1.21–1.29) compared with those with euthyroidism. Granular examination of thyroid statuses showed that hypothyroid and attenuated-hypothyroid statuses had CKD ORs (95% CI) of 1.59 (1.52–1.66) and 1.12 (1.08–1.16), respectively. A similar relationship was observed in analyses that defined CKD as an eGFR <60 L/min/1.73 m2. Among individuals 55 years and older, we observed that those with hypothyroidism were more likely to have CKD. A stronger association was found among patients of hypothyroid status compared with attenuated-hypothyroid status suggesting a dose dependent relationship.

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MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

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